PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a major public health concern associated with significant morbidity and mortality. Although MDD often emerges in adolescence, research in this age group remains scarce. The heterogeneity of adolescent MDD has further hampered identification of the disorder?s neurobiological underpinnings. To address these challenges, this research training fellowship utilizes a dimensional approach focusing on the core MDD symptom of anhedonia?the reduced capacity to experience pleasure. Anhedonia severity is highly variable in adolescent MDD, with increased severity predicting poor prognosis and suicide. Our research aims to delineate reward circuitry deficits associated with anhedonia. Converging preclinical data suggest that hyperactivity of the habenula (Hb), a small limbic hub, may underlie such deficits by excessively inhibiting reward signaling by the Ventral Tegmental Area (VTA) and downstream Nucleus Accumbens (NAc). Characterizing and even visualizing these regions in vivo has been a challenge in humans, however, due to technical constraints in magnetic resonance imaging (MRI). The propose research aims to comprehensively examines these critical reward regions using high resolution functional MRI approaches spearheaded by the Human Connectome Project (HCP) and high-fidelity analysis techniques. The project is supported by substantial data from our laboratory documenting a wide range of anhedonia severity in adolescent MDD, as well as relationships between anhedonia severity and intrinsic functional connectivity (iFC) of the NAc with the Anterior Cingulate Cortex (ACC). More recently, we reported iFC of the Hb with targets including the VTA and ACC in healthy HCP subjects; moreover, subjects with high vs. low subclinical depression scores exhibited distinct iFC patterns with regions associated with MDD, including the amygdala and insula. This study therefore proposes to examine the role of the Hb and VTA, as well as the NAc and cortical regions, in human reward circuitry and test the overall hypothesis that alterations in this circuitry are associated with MDD and anhedonia. We will examine high resolution resting-state and reward task fMRI data from (Aim 1) healthy young adult HCP subjects and (Aim 2) 35 psychotropic-medication free adolescents with MDD and 20 matched controls (ages 12-18, Tanner stage ? 4). Study procedures for adolescents will include diagnostic evaluations, dimensional measures of anhedonia, and an MRI session. Analyses will focus on the Hb, VTA, NAc, and cortical reward regions, examining iFC, activation during specific reward processes, group differences, and associations with anhedonia severity. SIGNIFICANCE: The proposed research addresses the heterogeneous nature of adolescent MDD by focusing on a narrow phenotype of anhedonia to examine the role of critical reward circuitry. The proposed multimodal training will provide experience in both clinical translational research and advanced imaging methodologies. This line of work has the potential to inform etiological models, improve diagnostics, and facilitate the development of targeted interventions.